The copper(II) complexes of new anthrahydrazone ligands: In vitro and in vivo antitumor activity and structure-activity relationship
| Autor: | Yan-Cheng Liu, Chen-Yu Wang, Zhen-Feng Chen, Hong Liang, Rui-Xue Liu, Wu Yingshu, Meng-Ting Tang, Ru-Yi Luo, Xiao-Hong Jiang |
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| Rok vydání: | 2020 |
| Předmět: |
In Vitro Techniques
Ligands 010402 general chemistry 01 natural sciences Biochemistry Inorganic Chemistry Mice Structure-Activity Relationship Coordination Complexes Cell Line Tumor medicine Animals Structure–activity relationship Binding site Cytotoxicity Cisplatin biology 010405 organic chemistry Chemistry Topoisomerase Liver cell Hydrazones Cell cycle 0104 chemical sciences biology.protein Pharmacophore Copper medicine.drug |
| Zdroj: | Journal of Inorganic Biochemistry. 212:111208 |
| ISSN: | 0162-0134 |
| DOI: | 10.1016/j.jinorgbio.2020.111208 |
| Popis: | Two new copper(II) complexes, 9-PMAH-Cu (1) and 9-FPMAH-Cu (2), of anthrahydrazone were synthesized and structurally characterized, in which 9-FPMAH (9-(4'-trifluoromethyl)-pyrimidine anthrahydrazone) is the 4'-CF3 derivative of 9-PMAH (9-pyrimidine anthrahydrazone). Both complexes 1 and 2 showed similar intercalative binding modes towards DNA and might compete with the typical DNA intercalator, GelRed, in the same binding site. They could also act as topoisomerase (type I) suppressor to effectively inhibit its activity, in which complex 1 was more effective than 2. The in vitro antitumor screening indicated that complex 1 displayed much higher antiproliferative ability than 2 and cisplatin towards all the tested tumor cell lines. On the other hand, complex 1 also showed high cytotoxicity against human normal liver cell line HL-7702, suggesting it is a potential high cytotoxic antitumor candidate. While it was also suggested that the loss of activity of complex 2 might be due to the presence of 4'-CF3 on the pyrimidine ring. Studies on the cellular level showed that complex 1 could arrest the cell cycle of the most sensitive T-24 cells at G2/M phase and induced cell apoptosis. Complex 1 further showed a significant suppression on the tumor growth on the T-24 tumor xenograft mouse model, but not reduced the body weight. Especially, complex 1 could retain its coordination state in H2O even in the presence of HSA. The results suggests that complex 1 is of enough safety to be considered as a promising anticancer candidate by combining the bioactive Cu(II) and the anthrahydrazone pharmacophore. |
| Databáze: | OpenAIRE |
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